Search

American journal of nephrology 52(10/11), 827-836 (2021). doi:10.1159/000519812, Published by Karger, Basel [u.a.]

Background: The role of serum uric acid (SUA) level in the progression of Immunoglobulin A nephropathy (IgAN) remains controversial. Methods: In a cohort of 1,965 cases with biopsy-proven IgAN, we examined the associations of SUA concentration with the primary outcome of a composite of all-cause mortality or kidney failure (defined as a reduction of estimated glomerular filtration rate [eGFR] by 40% from baseline, requirements for dialysis and transplantation), or the outcome of kidney failure alone, assessed using Cox and logistic regression models, respectively, with adjustment for confounders. Results: At baseline, the mean age was 33.37 ± 11.07 years, eGFR was 101.30 ± 30.49 mL/min/1.73 m2, and mean uric acid level was 5.32 ± 1.76 mg/dL. During a median of 7-year follow-up, 317 cases reached the composite outcome of all-cause mortality (5 deaths) or kidney failure (36 cases of dialysis, 5 cases of renal transplantation, and 271 cases with reduction of eGFR by 40% from baseline). After adjustment for demographic and IgAN specific covariates and treatments, a higher quartile of uric acid was linearly associated with an increased risk of the primary outcome (highest versus lowest quartile, hazard ratio [HR] 2.39; 95% CI 1.52–3.75) and kidney failure (highest versus lowest quartile, HR 2.55; 95% CI 1.62–4.01) in the Cox proportional hazards regression models. In the continuous analysis, a 1 mg/dL greater uric acid level was associated with 16% increased risk of primary outcome (HR 1.16, 95% CI 1.07–1.25) and 17% increased risk of kidney failure (HR 1.17, 95% CI 1.08–1.27), respectively, in the fully adjusted model. The multivariate ­logistic regression analyses for the sensitive analyses drew consistent results. In the subgroup analyses, significant interactions were detected that patients with mean arterial pressure (MAP) < 90 mm Hg or mesangial hypercellularity had a higher association of SUA with the incidence of the primary outcome than those with MAP ≥90 mm Hg or those without mesangial hypercellularity respectively. Hyperuricemia was not significantly associated with the risk of developing the primary outcome in elder patients (≥32 years old), patients with eGFR < 90 mL/min or with tubular atrophy/interstitial fibrosis. Conclusions: SUA level may be positively associated with the progression of IgAN. It was noticeable that the association of hyperuricemia with IgAN progression was less significant in patients with elder age, lower eGFR, or tubular atrophy/interstitial fibrosis, which may be due to some more confounders in association with the IgA progression in these patients. Future prospective studies are warranted to confirm these findings and to investigate the underlying mechanisms.

Background: Hydroxychloroquine (HCQ) is a well-known immunomodulator that is useful as in the treatment for lupus because of its inhibitory effect on toll-like receptors and cytokines, which are speculated to play a role in the pathogenesis of Immunoglobulin A (IgA) nephropathy (IgAN). However, there was only one study that investigated the effect of HCQ on proteinuria in patients with IgAN. Methods: Ninety patients with IgAN who received HCQ in addition to optimized dosage of renin-angiotensin-aldosterone system inhibitors (RAASi) were recruited for this study, and 90 matched historical controls who received RAASi alone were selected from our registry by the propensity score matching method. Their clinical data were compared at baseline and during follow-up till the termination of HCQ or addition of immunosuppressive agents. Results: The median baseline proteinuria level of the 90 patients who received HCQ was comparable with the RAASi-alone group (1.5 [1.2, 2.1] vs. 1.5 [1.2, 1.9] g/day, p = 0.74). At 6 months post-study initiation, the median proteinuria level in the HCQ group was lower than that in the RAASi-alone group (0.8 [0.7, 1.2] vs. 1.2 [0.8, 1.8] g/day, p = 0.02). The percentage by which proteinuria was reduced in the HCQ group was significantly higher than that in the RAASi-alone group (–43% [–57, –12] vs. –19% [–46, 17], p = 0.01). No serious adverse effects were documented during treatment with HCQ. Conclusion: The addition of HCQ to RAASi resulted in a significant and safe reduction in proteinuria in patients with IgAN.

Background: Crescentic IgA nephropathy (CreIgAN) has a poor prognosis despite aggressive immunosuppressive therapy. The efficacy of plasma exchange (PE) in CreIgAN is not well defined. Methods: Twelve patients with severe CreIgAN who received PE as addition to routine immunosuppressive therapy, followed for more than 6 months, were involved. Twelve matched historical controls who received immunosuppressive therapy alone were selected by propensity score matching. Renal survival, plasma IgA-IgG complex and active complement products were assessed. Results: Nine men and 3 women received a median of 7 PE courses (range 5-10). Their baseline urine protein excretion rate was 5.8 (4.5-8.7) g/day, and their serum creatinine level was 705.3 ± 296.4 μmol/l. During a mean follow-up of 15.6 months (6-51 months), 6 of the 12 PE group patients were free of dialysis, while all the control patients were dialysis dependent (6 of 12 vs. 0 of 12, p = 0.014). In the PE group, dialysis had to be restarted for 1 patient owing to the development of severe pneumonia and pulmonary failure. PE was associated with a higher kidney survival rate (log rank test, p = 0.026) during follow-up. It also significantly decreased plasma IgA-IgG complex levels (pre-PE: 85.3 ± 25.9% vs. post-PE: 38.4 ± 12.4%, p < 0.001) and plasma and urinary active complement product levels, including C3a, C5a and soluble C5b-9. The latter levels remained low until the last follow-up. Conclusion: This study indicated that PE could increase renal recovery rates in severe CreIgAN.

Background: Tacrolimus has been reported to be effective in refractory nephrotic syndrome, such as focal segmental glomerulosclerosis and membranous nephropathy. Some IgA nephropathy (IgAN) patients with massive proteinuria showed resistance to steroids and/or cytotoxic immunosuppressants based on the supportive therapy with renin- angiotensin system blockade. The efficacy and safety of tacrolimus in such refractory IgAN patients are extremely ambiguous, and the mechanism of tacrolimus improving proteinuria remission needs to be investigated. Methods: 14 refractory IgAN patients were enrolled. The patients received tacrolimus (0.05–0.1 mg/kg/day) and prednisone (0.5 mg/kg/day) for at least 6 months. Synaptopodin and calcineurin expression were detected in renal tissues of patients who received re-biopsy. A puromycin aminonucleoside (PAN)-induced human podocyte injury model was applied to investigate the possible role of tacrolimus in proteinuria remission. Results: Of the 14 patients enrolled, 3 were withdrawn because serum creatinine increased over 30% baseline. In 11 patients treated with tacrolimus over 6 months, 9 showed complete or partial remission and 7 achieved remission within 1 month. In renal tissues, the expression of calcineurin increased while synaptopodin decreased and recovered partially after tacrolimus therapy. In an in vitro study, F-actin disrupted in human podocytes after stimulation of PAN, while calcineurin increased and synaptopodin decreased. After co-treatment with tacrolimus the reorganization of F-actin and the expression of calcineurin and synaptopodin recovered. Conclusions: Tacrolimus showed a rapid proteinuria remission in refractory IgAN patients. The possible mechanism of tacrolimus to proteinuria remission might be podocyte cytoskeleton stabilization through inhibition of calcineurin expression.

MUC20, an upregulated novel gene in the renal tissues of patients with IgA nephropathy (IgAN), was recently identified. The variable number of tandem repeats (VNTR) polymorphism of the MUC20 gene was detected in several cell lines. In the present study, we investigated a possible association of MUC20 VNTR polymorphism with the clinical manifestations and progression in patients with IgAN. A total of 1,147 Chinese subjects, including 657 patients with IgAN and 490 geographically matched healthy controls, were involved in this investigation. One hundred and thirty-seven patients had been followed up for 60.6 ± 22.4 months. MUC20 VNTR polymorphism was genotyped by polymerase chain reaction amplification and confirmed by sequencing. The alleles were divided into two groups according to the repeat times of MUC20 VNTR, i.e. small alleles (VNTR repeat times ≤3) and large alleles (VNTR repeat times >3), and the genotypes of subjects were classified into SS, SL and LL groups. The frequencies of the alleles and genotypes of MUC20 VNTR polymorphisms did not differ between patients with IgAN and healthy controls. Additionally, there was no significant difference in the clinical features. Furthermore, IgAN patients with SL/LL genotypes had a higher risk of decline in renal function (odds ratio 20.9; 95% confidence interval 2.6–168.1; p = 0.004) than those with SS genotypes. The present study revealed that there is no association between the VNTR polymorphism of the MUC20 gene and the clinical manifestations in IgAN patients at the time of renal biopsy. However, IgAN patients with SL/LL genotypes had a higher risk of the progression to end-stage renal disease.

MUC20, an upregulated novel gene in the renal tissues of patients with IgA nephropathy (IgAN), was recently identified. The variable number of tandem repeats (VNTR) polymorphism of the MUC20 gene was detected in several cell lines. In the present study, we investigated a possible association of MUC20 VNTR polymorphism with the clinical manifestations and progression in patients with IgAN. A total of 1,147 Chinese subjects, including 657 patients with IgAN and 490 geographically matched healthy controls, were involved in this investigation. One hundred and thirty-seven patients had been followed up for 60.6 +/- 22.4 months. MUC20 VNTR polymorphism was genotyped by polymerase chain reaction amplification and confirmed by sequencing. The alleles were divided into two groups according to the repeat times of MUC20 VNTR, i.e. small alleles (VNTR repeat timesor = 3) and large alleles (VNTR repeat times3), and the genotypes of subjects were classified into SS, SL and LL groups. The frequencies of the alleles and genotypes of MUC20 VNTR polymorphisms did not differ between patients with IgAN and healthy controls. Additionally, there was no significant difference in the clinical features. Furthermore, IgAN patients with SL/LL genotypes had a higher risk of decline in renal function (odds ratio 20.9; 95% confidence interval 2.6-168.1; p = 0.004) than those with SS genotypes. The present study revealed that there is no association between the VNTR polymorphism of the MUC20 gene and the clinical manifestations in IgAN patients at the time of renal biopsy. However, IgAN patients with SL/LL genotypes had a higher risk of the progression to end-stage renal disease.